Production of secondary amines from nitrogen compounds



Patented Nov. 6, 1945 PRODUCTION OF SECONDARY AMINES FROM NITROGEN COMPOUNDS William S. Emerson, Dayton, Ohio No mowing. Application September 15, 1944, Serial No. 554.331

Claims. (Cl. 280-577) are formed to the exclusion or suppression oi The present invention relates to the reductive aikylation of amines, nitro, nitroso and azo compounds by means of aldehydes or ketones and hydrogen gas in the presence of a hydrogenation catalyst. The invention relates particularly to alkylation in the nitrogen-containing radical of the amino, nitro, nitroso or azo compound to produce N-alkyl or N-aralkyl substituted amines. The invention also relates to methods 01 controlling the proportion of secondary and tertiary amines produced in such reactions and is speciflcally directed to the production oi secondai'i and tertiary amines.

The principal objects of the present invention are to provide aasimple and economical method of obtaining N-alkylated or N-aralkylated amines by the reduction with hydrogen of an aldehyde or a ketone and an amine, nitro, nitroso, or aao compound or an intermediate condensation product of the specified carbonyl compounds and one of the nitrogen compounds. Another object of the invention is to provide a method oi such reductive alkylation of nitrogen compounds whereby the yield of secondary N-monoalkylated or tertiary N-dialkylated amines may be controlled to the extent of suppressing or entirely eliminating the formation of the undesired alkylated amines.

Other objects and advantages of the invention. .1

/some of which are specifically referred to here inafter, will be apparent to those skilled in the art.

This application is a continuation-in-part of Patent No. 2,298,284, of which my co-pending appllcation Serial No. 370,355 is a continuation-4npart, I have disclosed that by reducing a mixture of an aldehyde and a nitro or amino compound with hydrogen in the presence of a platinum or Raney nickel reduction catalyst under neutral or slightly alkaline reaction conditions, secondary amines are formed while the simultaneous formation of tertiary amines is suppressed or entirely avoided. Such neutral or slightly basic or alkaline conditions are obtained by placing in the reaction mixture undergoingv hydrogenation an alkali-metal salt of a weak organic acid such as sodium acetate, sodium carbonate, sodium stearate or the like. I have also shown in my co-pending application Serial No. 370,355 and in my application Serial No. 332,975 that if acid conditions are maintained in a similar reaction mixture, for example, by the presence of trimethylamine hydrochloride in the reaction mixture, tertiary mines secondary amines.

I have discovered that in such reductive alkylations with nitrogen compounds and carbonyl compounds,' that neutral or slightly basic reaction conditions maintained by the addition of sodium acetate or other alkali-metal salts of weak organic acids favor the formation of se ondary amines while acid conditions maintained the addition of trimethylamine hydrochloride, acetic acid or the like, iavor the formation 01 tertiary amines. 1 Although I refer to neutral or basic and acid condition or media throughout this specification, it is not to be understood that acidity or alkalinity in and of itself is directly responsible for the improvements specified. Sodium acetate, acetic acid or trimethylamine hydrochloride do change the pH or hydrogen-ion concentration of the reaction mixture but they probably act by virtue of their ability to favor certain condensation reactions or the like rather than as a result or their acidity. Sodium hydroxide, for example, which produces alkaline media, hinders reaction. Hence %it is to be understood that when acid or basic media or conditions are referred to, these terms are used merely ior convenience to classify the various kinds of condensing agents which are added to the reaction mixture.

when the carbonyl compound used in such reactions is a ketone instead of an aldehyde, somewhat more' drastic reaction conditions, such as higher temperatures, are necessary to produce secondary amines in neutral or slightly basic media. Ketones do not yield tertiary amines in neutral or slightly basic media. In acid media, on the other hand, ketones yield secondary instead oi tertiary amines, even under drastic reaction copditions such as elevated temperatures of reaction and concentrated acid.

I have' also discovered that besides amines and nitro c mpounds, other nitrogen compou s such as nit use and azo ompounds, for example, nitrosobenzene and azo enzene, may be usedin the reactions. Furthermore, I have foundfthat substituents such as hydroxyl and aminoradlcals in the nitrogen compound have an activating eiiect on the reaction. Thus. when an aromatic nitrogen compound contains an amino or a hydroxyi group ortho, or particularly, para, to the nitro, amino, nitroso or azo group, the reductive alkylation of such substituted compound with ketones progresses more rapidly to the formation of secondary amines while with aldehydes, reaction is also accelerated and tertiary amines are termed in either basic or acid media. Alkyl groups substltuted in the benzene ring also have a mild activating influence which is less pronounced than that of amino or hydroxyl groups, however. In the case of am compounds, hydroxy or dimethylamine groups, either ortho or para to the azo group, have an activating influence and tertiary amines are formed in alkaline or acid media.

The methods of adopting the present discovcries and those of my co-pending application, Serial No. 370,355 and my application Serial No. 332,975, to the production of secondary or tertiary amines by reductive alkylation are set forth in the examples which follow hereinafter, but may be briefly summarized as follows:

A. Secondary amines may be made by the reaction or hydrogen in the presence of a hydrogenation catalyst on a reaction mixture comprising:

1. An unsubstituted nitrogen compound (nitro, amino, nitroso or azo compound) or such a nitrogen compound free from activating substituents such as amino or hydroxyl groups in the ortho or para position, together with an aldehyde, in an alkaline medium (activating substituents favor the formation of tertiary amines), or

2. A nitrogen compound containing activating substituents together with a ketone in an acid medium, or less favorably, in an alkaline medium, or v 3. An unsubstituted nitrogen compound or a nitrogen compound free from activating substituents, as in 1, together with a ketone in an acid medium or in an alkaline medium under more drastic reaction conditions.

8. Tertiary amines may be made by the reaction 01 hydrogen in the presence of a hydrogenation catalyst on a reaction mixture comprising:

l. A nitrogen compound (nitro, amino, nitroso or azo compound), with or without activating substituents, together with an aldehyde in acid media. or

2. A secondary amine together with an aldehyde in an acid medium.

Ketones are inactive or are not as reactive as aldehydes in the formation of tertiary amines, either in acid or alkaline media, even under drastic reaction conditions. They may be advantageously used, however, in the production of secondary amines in accordance with the processes summarized above, especially when used in an acid instead of an alkaline medium. The reaction of primary aromatic amines with aldehydes, particularly formaldehyde, in acid media, is complicated by the formation of tarry condensation products of the type of anhydroformaldehydeaniline and the like and hence, to avoid such formation of condensation products, resort should be made to primary aromatic nitro compounds er the like as starting materials; such condensation products do not readily form between primary aromatic amines and ketones or secondary aromatic amines and either aldehydes or ketones and hence reaction mixtures containing these compounds may be used. When formaldehyde is used in any reaction mixture under acid conditions, complications are also likely to result from polymerization of the formaldehyde. These complications do not result with acetaldea,ses,ccs

hyde or higher aldehydes when used in the acid reaction mixtures contemplated by the present invention, however. The reductive alkylation product of formaldehyde and primary aromatic amines. furthermore, is a tertiary amine. in many cases, even in alkaline reaction media.

The yields in the foregoing alternative processes for the production of secondary or tertiary amines vary somewhat and hence one will be preferable to another. The processes also diil'er in the proportion of secondary or tertiary amines which are iormed. By using ketones to prepare secondary amines, for example, it is possible to operate in such a manner that no substantial proportion of tertiary amine is formed as a byproduct, which may be highly desirable, whereas in a reaction where the tertiary amine is the desired product it may be more economical to adopt an alternative which gives a high yield of tertiary amine that may be contaminated with small proportions of secondary amines in preference to one which gives a small yield of tertiary amine uncontaminated with secondary amines, since secondary amines can be converted in a separate subsequent step to tertiary amines.

It is known that secondary and tertiary amines have been prepared by reductive alkylation by the use of nascent hydrogen generated in situ from the reaction of a metal and an acid or by the use 01' hydrogen gas in the presence oi a nickel catalyst at high temperatures (50 to 200 C.) and under high pressures (50 to 150 atmospheres). That such reactions could be conducted with hydrogen gas in the presence of a hydrogenation catalyst under relatively mild reaction conditions (room temperature and pressures of about 2 to 4 atmospheres) by the use of the specifled acids or salts which modify the acidity (pH or hydrOBen-ion concentration) of the reaction medium and serve as condensing agents 01' mod-- ify the reaction in some other manner, was unexpected.

By means of the processes of the invention it has been possible to prepare in an advantageous manner amines which have not been heretofore prepared or which could not be prepared by heretoi'ore known methods. Since. the methods disclosed herein show how alkylation may be stopped at the formation of the secondary amine the methods are useful for the preparation of tertiary amines having two different alkyl substituents on the amino nitrogen atom in an advantageous manner.

In the examples which follow, typical methods of practicing the process of my invention are set forth:

Example I.N-Ethulaniline using acetolhedude and alkaline conditions Into an apparatus for catalytic reduction, pref erably provided with a stirrer or means for shaking, are placed 93 grams (about i moi) of aniline dissolved in 1500 cc. of 95% ethyl alcohol and about 88 grams (about 2 mols) of acetaldehyde, 10 to 20 grams of fused sodium acetate, and about 30 grams of Raney nickel catalyst, which may be prepared by the method of Covert and Adkins described in the Journal of the American Chemical Society, 1932, vol. 54, page 4116. Other methods of preparing Raney nickel catalysts are described in U. S. Patents 1,563,587; 1,628,190; 1,915,473; and 2,139,602. The apparatus is evacuated and then an initial pressure of about 3 at mospheres (45 lbs. per square inch) or hydrogen is applied. The apparatus is maintained at room Example IL-N-n-hetflvlmiliae using heptaldehvdc and alkaline conditions By proceeding as in Example I, using from 2 to 5 mols oi heptaldehyde instead of acetaldehyde and fractionsting the product in vacuum. N-n-heptylanlline is obtained.

N-n-heptylaniline has a boiling point of 125 to 130' C. at a pressure of 30 mm., a specific gravity of 0.906 at l20 C. and a refractive index at 20 C. of 1.5080 for the sodium D line.

Example III. N-n-butyl-alpha-naphthulamine using bum-aldehyde and alkaline conditions By proceeding as in Example I but substituting butyraldehyde for acetaldehyde and alpha-naphthylamine for aniline in molecular proportions, and fractionating the product in vacuum, N-nbutyl-alpha-naphthylamine is obtained in 80% of the theoretical yield. 7

The new compound, N-n-butyl-aipha-naphthylamine, has a boiling point of 155 to 167 C. at a pressure of 8 mm, a specific gravity of 1.004 at 20720 and a refractive index of 1.5903 at 20 C. for the sodium D line. Its hydrochloride melts at 151 to 152 C.

Example lV.-N-ethyl-p-anisidine using acetatdehi/de and alkaline conditions By proceeding as in Example I but substituting p-anisidine for aniline in molecular proportions and fractionatirig the product, N-ethyl-panisidine is obtained in 51% yield.

N-ethyl-p-anisidine has a boiling point of 135 to 140' C. at a pressure or 20 mm., a speciilc gravity of 1.0l7at 20720 and a refractive index of 1.5444 at 20 C. for the soduim D line. Its parabromobenzenesulionamide melts at 113 to 114 C.

' Example V.N-n-butvl-p-aaisidine using bulwaldehvdc and alkaline conditions By substituting butyraldehyde for acetaldehvde in molecular proportions in Example IV and proceeding as therein described, N-n-butyl-p-anisidine is obtained in 65% yield.

This new compound, N-n-butyl-p-anisidine, has a boiling of 142 to 145 C. at a pressure of 8 mm., a specific gravity of 0.963 at 20l20 and a refractive index of 1.520? at 20' C. for the sodium D line. Its hydrochloride melts at 187.5

Example VL-N-n-butplaniline from nitrobenzone and butvraldehvde under alkaline conditions Into an autoclave provided with a stirrer are placed 123 arms (about 1 mol) of freshly distilled nitrobenzene, 20 grams of fused sodium acetate, 1500 cc. of 95% ethyl alcohol, 94 grams (about 1.3 mol) of freshly distilled n-butyraldehyde and grams of Raney nickel catalyst. The autoclave is evacuated and thereafter an initial pressure of 3 atmospheres of hydrogen is applied to the autoclaveand the mixture is maintained at room temperature. Alter about 4 mole of hydroaen have been absorbed. the reduction is stopped and the catal-yst is removed by filtration or decantstion. The filtrate is made slightly acid with hydrochloric acid and the alcohol is distilled ofl. The residue is then diluted with about 1000 cc. of water and made slightly alkaline with sodium hydroxide. It may be subsequently extracted with ether and the extracts combined and after evaporation of the ether, fractionally distilled. However, the original residue without dilution with water may be made basic and then subjected to vacuum distillation. The product. N-n-butylaniline. is obtained in a yield of about 17% to 81% of the theoretical and has a boiling P int of 235 to245' 0.

Example VII-N-di-n-butyl-p-aminophenol from p-niirophenol and butilraldelwde under alkaline conditions When p-nitrophcnol is substituted in Example V1 for nitrobenzene and butyraldehyde is present in excess, the product obtained is substantially all N-di-n-butyl-p-aminophenol. It is diiiicult to get any yield of secondary amine in this reaction because or the pressure of the activating hydroxyl group in the para position.

Example VIIL-p-Chlgro-a-butylanilinc from pchloroaitrobeneene and batilraldelwde under alkaline conditions By substituting p-chloronltrobenzene for nitrobenzene in molecular proportions in Example VI. the product obtained consists of unsltylated pchloroaniline. a fraction boiling at 105' to 145 C. at 25 mm, consisting of n-lmtylsniline and p chloro-n-butylaniline, and higher boiling fractlons in which occurs p-chloro-n-butylaniline.

The yield in this case indicates that chlorinesubstltuents have no activating influence since the yield is substantially identical with that obtained when nitrobenzene is reacted under the same conditions. The lack of activating influence of the chlorine is shown more than anything else by the presence of unalkylated p-ohloroaniline in the reaction mixture.

Example IX.--N-di n-heptvl-p-tolaidine from pnitroioluene and/heptaldehude under alkaline conditions 1 retical. The latter compound, N-di-n-heptyl-ptoluidine, is a new compound and has a boiling point of to 200 C. at a pressure of 2.5 mm.. a specific gravity of 0.943 at 20720 and a refractive index of 1.5089 at 20 C. for the sodium D line. Its hydrochloride melts at 136 C. The methyl group of the riitrotoluene has a mild activoting influence, the formation of both secondary and tertiary amines being a result thereof.

Example X.-N-ethplaailine using ace'taldehude, alkaline conditions and platinum catalyst By substitutin 2 grams of a platinum oxide catalyst prepared according to the method of Adams. Voorhees and Shriner ("Organic Byntheses," coll. vol. 1 1932, page 452) for the Haney nickel catalyst and proceeding otherwise as in 4 a,ses,oos

Example I, N-ethylaniline is obtained in a yield oi 41% oi the theoretical.

Example XI-N beneul alpha naphtlwlamine using benzaldehyde and alkaline conditions By substituting benzaldehyde tor acetaldehyde and alpha-naphthylamine ior aniline in molecular proportions in Example I end=proceeding as otherwise therein indicated, benzyl-alpha-naphthylamine is obtained. Its benzamide has a melting point of 103 to 104 C.

Table I .Reductive alkylation of nitrobenzene with. hum-aldehyde in media. varying acitities The eiIect or various oi the added agents and of nitrobenzene in the presence of 3 grams of Raney nickel catalyst. The pH represents the acidity of the reaction mixture as observed on a Hellige pH meter. The yields are expressed as per cent 01 secondary (N-n-butylanlline) and tertiary amines (N-di-n-butyianiline) respectively.

O. by Reilly and Hickinbottom, J. Chem. Soc. of London, 1918, vol. 113I page 99.

Example XIIL-N-n-di-n-butylaniline using nitrobenzene and acid conditions By using 3 grams of Raney nickel catalyst instead 01 the platinum catalyst in Example X11 and 2 grams of trimethylamine hydrochloride instead of the acetic acid, and using 36.9 grams (0.3 mol) oi nitrobenzene, so that the ratio of nitrobenzene to butyraldehyde is 1:1. a yield of 68% N-di-n-butylaniline is obtained. (The yield is 98% based on the aldehyde consumed.)

The use 01' larger ratios oi aldehyde in this pre aration results in lower yields of the tertiary amine.

Example XIV.-Tertiaru amines using nitro com pounds, acid conditions and platinum catalysts Adopting the method of Example m, usin glacial acetic acid to provide the acid medium and platinum catalyst and substituting the appropriate aldehyde and ultra compound, the following yields of the respective aliphatic and aromatic tertiary amines were obtained. (Melting points of h g b Per cent yield y mu yr- Run gen ab aldehyde Solvent Condensing agent pH 8600mm Tertiary sorbed Pr n amine amine 0. 56 0. 8. 81 0. 42 0.10 .d 8. 81 0. 42 0. l2 8. 81 0. 30 0. l8 8. B1 0.44 0.13 3,31 0.40 0.13 0 7.41 0. 41 0. 13 Alcohol 2 g. trimethyl amine hydrochloride. 4. 13 0. 42 0.13 ...do 2 g. sodium lormate 8. 44 0.41 0.13 do 2 g. sodium carbonate 9. 22 0. 43 0.13 dc 5 cc. trimetbylamine 0.

Example XlI.-N-di-n-butulaniline using nitrobenzene, acid conditions and platinum catalyst Into the pressure bottle of a machine for cataly'tic reduction is placed a solution of 12.3 grams (0.1 mol) of nitrobensene, 21.6 grams (0.3 mol) of butyraldehyde and 10 cc. of glacial acetic acid in cc. of 95% ethyl alcohol. To this solution was then added 0.1 gram of platinum oxide catalyst prepared according to the method of Adams, Voorhees and Shriner ("Ol'flanic Syntheses," collective volume I, 1932, page 452) and the mixture was shaken on the machine for 96 hours during which time 0.66 mol of hydrogen was absorbed. After this hydrogenation the mixture was acidified with 17 cc. oi dilute hydrochloric acid and the plat'num catalyst was removed by filtration. The alcohol was evaporated from the filtrate, the residue was 7 derivatives used for identification purposes are listed in last column.)

The properties of the respective amines thus prepared were as follows:

Bpeciiic Refractive Boiling range gravity index ("n") 4 m m tyimethglsmine" -163 C 0.782 1.4302 6 Ndpmpmp lmet ylamine. 110-122 C 0. 743 1.4076 3 N-digthyba pha naphthylltd- 0.]30 mm"... 1. 016 1. 5961 am no.

then made alkaline with sodium hydroxide and extracted with ether. The ether was removed from the ether extract and the product was distilled. The boiling range of the N-di-n-butyianiline was 265 to 215 C. and 14.5 grams of the 7 Example XV.--N-isopropplaniline using acetone and acid conditions substituting acetone for the acetaldehyde used in Example XII in equimolecular amount and proceeding as otherwise therein described, a secondary amine, N-isopropylaniline, instead of a tertiary amine, was obtained in 54% yield. The N-isopropylaniline had a. boiling range of 198 to 207 C. and formed a benzamide derivative hav- The melting point 0! the picra'te is given as 125" ing a melting point of as" to as c.

o,sse,eos

Example XVL-N-isopropylmeihulomine using custom and cold conditions Acetone and nitromethane when reacted according to the procedure of Example XII, produced N-isopropylmcthylamine in 59% yield. The product had a boiling range of 45 to 55 C. and was identified as a picrate having a melting point of 133 to 135 C.

Example XVII-N bensyl 1v nbatulaniline using N-benzulphenylhudroacylumine and acid conditions By using butyraldehyde and N-benzylanillne in the molecular ratio or 2:1 and hydrogenating in accordance with the procedure described in Example XII, N-benzyl-N-n-butylaniline was obtained in 3% yield, 64% oi the N-benzylaniline being recovered unchanged.

A larger and more satislactor yield (38%) or N-benzyl-N-n-butylaniline can be obtained by reacting butyraldehyde and N-benzylphenylhydroxylamine (which can be prepared by the method of Vavon and Craicinovic, Compt. rend., 1928, vol. 187, page 420) in the molecular ratio or 2:1 according to the procedure Example XII, using platinum catalyst and acetic acid in the reaction mixture.

N-benzyl-N-n-butylaniline dlstills at 175 to 182 C. at a pressure oi mm., and has a specific gravity (l20' C.) or 1.019 and a refractive index oi 1.5810 at 20 C. for the sodium 1) line. Its picrate had a melting point of 126 to 128 C.

By g sodium acetate instead of acetic acid and Honey nickel catalyst instead of a platinum catalyst, as in Example .I, N-benzylphenylhydroxylamlneand butyraldehyde in the molecular ratio or 1:2 produced N-benzylanillne in we yield without the formation of any quantity of the tertiary amine, N-benzyl-N-n-butylaniline, that could be isolated.

Example XVIII.N-n-butyloniline will! ozohenzene and alkaline medium Into a machine for catalytic reduction was placed a solution oi 18.2 grams (0.1 moi) of a20- benzene, 18.0 grams (0.25 mol) oi butyraidehyde and 2 grams of fused sodium acetate dissolved in 150 cc. of 95% alcohol. To this solution was then added about 10 grams or Haney nickel catalyst. From 2 to 40 grams or Raney nickel catalyst give satisfactory results but 10 grams give a smooth and rapid reduction. Hydrogen was passed into the mixture while the machine was shaking until 0.3 tic-0.4 me] had been taken up. th period required being approximately 1 to 2 hours. The catalyst was removed by filtration, the filtrate was acidified with hydrochloric acid and the alcohol was evaporated.

,The product was recovered by making the residue alkaline, extracting the alkaline residue with ether, drying the ether extract over sodium hydroxide and subsequently distillation. the extract.

The yield oi' N-n-butyianiiine, a secondary amine, was 71% and the product was identified as the p-bromobenrenesulionamide which had a melting point of 85 to 86 C.

Example XIX.N-n-heptulaniline using uzobenzene and alkaline medium Bubstitutlnfl an equivalent amount of heptaldehydo lor the butyraldehyde 0! Example XVIII and proceeding as therein otherwise indicated,

N-n-hcptylaniline was obtained in 74% yield 7 and was identified as the p-bromobenzenesulionamide having a melting point 0! 114 to 115 C. In the case or higher molecular weight amines, such as N-n-heptylaniline, the reaction mixture after hydrogenation need not be acidified before evaporation of the solvent (alcohol).

Example XX.N-benzulaniline using azobeneene and alkaline conditions By the procedure 01 Example XVIII, substitutmg benzaldehyoe in an equivalent amount for the butyraldehyde, N-benzylamline was obtained in 49% yield. The product, N-nenzylaniline, was identified as the hydrochloride, having a melting point of 210 to 212 C,

Example XXI .-N dimethyi N di-n-butyl-pphenylenediumine usma N-dimethul-p-aminoazooenzene and alkaline conditions secondary amine, as would be obtained under alkaline conditions with an unsubstituted azo compound, a tertiary amine is obtained. The activating influence of a hydroxy group is shown in the two next examples (XXII and XXIII).

Example XXIL-N di n buiui-p-aminophenoi using p-hydrozyozobenzene and alkaline conditions Substituting an equivalent amount of p-hydroxyazobenzene for the azobenzene in Example XVIII and proceeding as therein otherwise indicated, the tertiary amine, N-di-n-butyi-p-amimphenol, was obtained in 46 yield. The product was} isolated as the benzoate by treating the react on mixture with benzoyl chloride and aqueous alkali.

The benzoate oi N-di-n-butyl-p-aminophenoi, alter recrystallization irom acetic acid, has a melting point of 232 to 233 C.

Example XXIII .1 (N di n butulomino) -2- naphthol using .l-phenulazo-Z-naphthol and alkaline conditions Utilizing the procedure oilllxample XVIII, by substituting l-phenyiazo z-naphthol for azobenzone in equivalent amount, the tertiary amine 1- (N -di-n-butylamino) -2-naphthoi was obtained in 41% yield. The product was isolated by adding water to the reaction mixture after hall of the I alcohol had been distilled.

l-(N-di-n-butylaminol -2-naphthol has a melting point of 106 to 107 C. and darkens rapidly on standing. It forms a hydrochloride that melts at 225 to 22"! C. and which is more stable than the tree amine.

The foregoing reactions with azo compounds may also be conducted in acid media to obtain a preponderance of tertiary amines.

Example XXlV.N-n-buiyianillne using nitrosobenzene and alkaline conditions Utilizing the foregoing procedures, N-n-butylaniline was obtained in 65% yield by the reductive alkylatlon of nitroscbensene (0.1 mall and butyraldehyde (0.1 mol) in the presence of Honey nickel catalyst grams) and sodium acetate (2 grams). Aniline is also recoverable from the reaction mixture.

Example XXlL-N-benzylaniline using nltrosobenzene and alkaline conditions Using the foregoing procedures, N-benzylaniline was obtained in 35% yield by the reductive alkylation 01 nitrosobenzene (0.1 mol) and benzaldehyde (0.1 mol) in the presence of Raney nickel catalyst (5 grams) and sodium acetate (2 grams). From the reaction mixture some aniline is also recoverable.

In the two foregoing examples (XXIV and XXV) the use of nitrcsobenzene in the reductive alkylation required larger quantities of catalyst than would be required for the corresponding reduction of nitro or amino compounds and the yields of secondary amines is lower and the product is contaminated with tars. The preparation of secondary amines from aromatic nitroso compounds requires a greater degree of control of the reaction than nitro or amino compounds.

Example XXVL-N-isopropylonilinc, using acetone, nltrobenzene and trimethylamine hydrochloride Substituting acetone for the acetaldehyde used in Example X11 in equimolecular amount, substituting grams of trimethylamine hydrochloride for the glacial acetic acid used in Example HI and proceeding as otherwise therein described, a secondary amine, N-isopropylaniline instead of a tertiary amine is obtained.

Example XXVII.--N-secondary butylaniline using methyl ethyl ketone, nltrobenzene and trimethvlamine hydrochloride Enample XXVlIL-N-cyclohexylaniiima, using cyclohcxanone, nltrobenzene and trimethyl hydrochloride Substituting cyclohexanone for the acetaldehyde used in Example XII in equimolecular amounts substituting 10 grams of trimethylamine hydrochloride for the glacial acetic acid used in Example XIII and proceeding as otherwise therein described, a secondary amine, N-cyclohexylaniline is obtained. N-cyclohexylaniline has a boiling point of 167 C. at 20 mm. and is slightly soluble in water.

The processes of the invention are applicable to the reductive alkylation of various nitrogen compounds, including aliphatic and aromatic amines such as methylamine, ethylamine, propylamines, butylamines, amylamines, aniline, ptoluidine, p-anisidine, alpha-naphthylamine, beta-naphthylamine, phenylpropylamines (phenyiaminopropanes) and the like; aliphatic and aromatic nitro compounds such as nitromethane, nitroethane, nitropropanes, nitrobutanes, nitropentanes, nitrobenzenes, nltrotoluenes, nitroaseacos phenols, nitroanisoles, chlorinated nitrobenzenes, nitronaphthalenes, nitronaphthols, nitronaphthylamines. phenylnitropropanes and the like; aromatic nitrosoamines such as nitrosobenzene and the like; and am compounds such as ambenzene and substituted azobenzenes such as N- dimethyl-p-aminoazobenzene, p-hydroxyazobenzene, l-pheny1azo-2-naphthol and the like. The nitrogen compounds may contain chlorine, alkoxy or aryloxy substitucnts, for example, chloroaminobenzenes, nitroanisoles, nitrodiphenyloxides and the like, which substltuents have no substantial activating influence. However, when amino, lnvdroxy or alkyl substituents are present, as previously mentioned, the compound is activated as a result thereof.

In the preparation of tertiary amines, N-monoalkylated secondary amines may be used as starting materials, as is obvious, especially when a tertiary amine with two diflerent substituents on the amino nitrogen atom is the desired product. As heretofore mentioned, the presence of activating groups in the nitrogen compounds particularly hydroxy, amino, and substituted amino groups, and particularly those para or ortho to the reacting nitrogen-containing radical, influence the degree of alkylation efiected and the ease of the reaction.

Carbonyl compounds which may be used in the reaction include both aliphatic as well as aromatic aldehydes and ketones. Aldehydes are more reactive than ketones, as heretofore mentioned, and ketones in most cases cannot be used to effect alkylation beyond the formation of secondary amines. Examples of aldehydes and ketones which may be used in the processes are formaldehyde, acetaldehyde, proplonaldehyde, butyraldehydes, pentaldehydes, hexaldehydes, heptaldehydes, benzaldehyde, acetone, ethyl methyl ketone, diethyl ketone, acetophenone, propiophenone and methyl phenyl dlketone and the like. Generally branched-chain or arboraceous aldehydes and ketones do not react as readily as straight-chain compounds. Formaldehyde, as heretofore mentioned, may lead to complications.

Although I have referred to alkyiation throughout this specification, it is to be understood that the term when used in the broad sense includes the introduction of aralkyl groups such as is eil'ected by the use 0! benzaldehyde and the like, as well as alkyl groups. The process of the invention, however, finds its greatest applicability in the case of aliphatic aldehydes whose use in such reactions has not heretofore been possible in a facile manner.

Although I have particularly referred to reaction mixtures containing carbonyl compounds and nitrogen compounds as starting materials, condensation products of the two, or intermediate products oi their reductive alkylation may be used.

As hydrogenation catalysts for the reduction, Raney nickel catalysts, platinum black, palladium black and platinum oxide and similar low-pressure hydrogenation catalysts are preferred. Catalysts such as copper chromite are not operative at the low temperatures and pressures contemplated by the present processes. When using acid conditions or reaction platinum oxide catalysts are preferred to Raney nickel catalysts. With respect to choice of catalyst, it is also to be noted that certain hydrogenation catalysts are more sensitive to chlorine and sulfur compounds than others and hence ii the compounds involved in any particular reaction contain halolen or suliur substituents, proper selection of a catalyst to avoid complications should be made. The Proportion of catalyst used for the reaction may be varied over a wide range, as illustrated in certain of the examples.

The alkaline conditions referred to in this specification may be obtained by the use 01' sodium acetate, sodium propionate, sodium butyrate, sodium stearate, sodium carbonate, and in general, other alkali-metal salts of weak organic acids, as disclosed in my co-pending application Serial No. 370,355 and my application Serial No. 332,975. Sodium hydroxide gives a lower yield of product than sodium acetate and in some cases completely suppresses aikylation, hence is to be avoided. Generally grams to or more grams of fused sodium acetate should be used for each mol of nitrogen compound taking part in the reaction and the yields are not materially changed by the presence of greater proportions. Fused sodium acetate is preferred but it is not essential that the salts used should be anhydrous.

Acid conditions referred to in this specification may be obtained by the use of acetic acid and other weak organic acids, trimethylamine hydrochloride and similar salts 01 strong (mineral) acids and weak organic bases, containing no alhvlatable hydrogen atoms attached to the nitrogen atom, preferably salts oi tertiary amines. Mineral acids such as hydrochloric acid and the like cannot be used advantageously. Approximately to 100 grams of glacial acetic acid, for example, to each mol ot reacting nitrogen compound should be used.

The reactions may be carried out in various solvents. The examples illustrate the use or 95% ethyl alcohol and dioxane as a solvent but ethyl acetate, methyl alcohol, isopropyl alcohol,-

isopropyl ether and the like may be used. The essential requisite oi the solvent is that it be inert in the reaction and that it dissolve the sodium acetate, trimethylamine hydrochloride or other agent used to facilitate the reaction.

The proportion of reactants in the reaction mixture is not oi paramount importance. Generally the carbonyl compound should be in excess of that required by the particular reaction which it is desired to effect.

The temperatures which may be used in the reactions vary from normal room temperatures to approximately 100 0., although the preferred range is about 10 to C. Generally the reaction will proceed without the addition or extraneous heat and with large batches cooling may be desirable to control the reaction. Likewise,

the pressures may be varied greatly, for example, from normal atmospheric pressure to 10 or more atmospheres. Preferred pressure conditions, however, are irom 2 to 4 atmospheres.

By interrupting the reductive alkylation of arematic nitrocompounds with aliphatic or aromatic aldehydes according to the present invention at an intermediate stage, it is possible to isolate substantial amounts 0! hydroxylamines. The media may be either acid or alkaline as herein described. These hydroxylamines can be rearranged with acids such as sulfuric acid to give the corresponding aminophenols. Hence, by this procedure I am able to produce substituted hydroxylamines and aminophenols in an advantageous manner. Furthermore, these intermediate products indicate the probable mechanism or reductive alkylation processes according to the invention. Briefly the reactions may be typified by that oi nitrobenzene and an aldehyde (ECHO) which may be represented as follows:

CHsR

CHIR

N-benzylplienylhydrorwlamine prepared by interrupting the reductive alkyiation of nitrobenaene with benzaldehyde, condenses with n-butyraldehyde in an acid medium to give N-benzyl-N-nbutylaniline. The yield is 38% when 2 mols or butyraldehyde are present to each mol of benzylphenylhydroxylamine (Example XVII).

As used herein and in the claims, the term "weak organic acid is to be understood to signify monocarboxylic aliphatic acids such as acetic acid, formic acid, propionic acid, butyric acid, dicarboxylic and polycarboxylic acids and the like and to distinguish irom strong organic acids such as benzene-sulionic acids and similar non-carboxylic acids and mineral acids.

Inasmuch as the foregoing description comprises preferred embodiments of the invention, it is to be understood that my invention is not to be limited thereto and that modifications and variations may be made therein to adapt the invention to other specific uses without departing substantially fromits spirit or scope as defined in the appended claims.

I claim:

1. The process of producing an N-alkylated amine comprising the hydrogenation of a mixture of two compounds, one of which is an organic nitrogen compound selected from the group consisting of primary and secondary aliphatic and aromatic amines, aliphatic and aromatic nitro compounds and aromatic nitroso and azo compounds, and the other 01 which is a ketone in the presence or a hydrogenation catalyst and a condensing agent consisting of a salt of a mineral acid and an organic base.

2. In the method of producing an N-alkylated organic compound by the hydrogenation in the presence of a hydrogenation catalyst 01' a mixture of two compounds, one of which is an organic nitrogen compound free from hydroxyl and amino substituents and selected from the group consisting oi primary and secondary aliphatic and aromatic amines, aliphatic and aromatic nitro compounds and aromatic nitroso and azo compounds, and the other of which is a ketone, the improvement comprising conducting the hydrogenation in the presence or a condensing agent consisting of a salt oi a mineral acid and an organic base.

3. The process as defined in clalmrl in which the condensing agent is trimethylamine hydrochloride.

4. The process as defined in claim 1 in which the hydrogenation catalyst is or the Honey nickel yp 5. The process of producing N-isopropyl aniline Hawk comprising the hydrogenation of a mixture or acetone and nitrcbenzcne in the presence or! a hydrogenation catalyst and trimethylamine hydrochloride at a temperature within the range or approximately 50' to 100 C. and at a pressure of approximately 1 to 4 atmospheres.

6. The process 01' producing N-sec-hutyl aniline comprising the hydrogenation of a mixture of methyl ethyl ketone and nitrobenzene in the presence or a hydrogenation catalyst and trimethyiamine hydrochloride at a temperature within the range of approximately 15" to 100 C. and at a pressure of approximately 1 to 4 atmospheres.

7. The process of producing an N-butylated aromatic amine comprising the hydrogenation of a mixture of a keton having 4 carbon atoms in its structure and an aromatic nitro compound in the presence of a hydrogenation catalystand a condensing agent consisting of trimethylamine hydrochloride.

CERTIFICA'E OF CORRECTION.

8. The process of producing an N-alkylated aromatic amine comprising the hydrogenation or a mixture oi an aromatic nitro compound WILLIAM S. EMERSDN.

November 6, 19 45- WILLIAM s. mason.

It is hereby certified that error appears in the printed specification of the above munbered patent requiring correction as follows: Page 3 secand column, line 27, for'"pressure" read --presenoe-; line 114., for "aoitities" read --aoi.dities--;

page it, first column, and that the said Letters Petent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 5th day of F ruary, A. D. 19146.

(Seal) Leslie Frazer i First Assistant Camissioner of Patents.

hydrogenation catalyst and trimethylamine hydrochloride at a temperature within the range or approximately 50' to 100 C. and at a pressure of approximately 1 to 4 atmospheres.

6. The process 01' producing N-sec-hutyl aniline comprising the hydrogenation of a mixture of methyl ethyl ketone and nitrobenzene in the presence or a hydrogenation catalyst and trimethyiamine hydrochloride at a temperature within the range of approximately 15" to 100 C. and at a pressure of approximately 1 to 4 atmospheres.

7. The process of producing an N-butylated aromatic amine comprising the hydrogenation of a mixture of a keton having 4 carbon atoms in its structure and an aromatic nitro compound in the presence of a hydrogenation catalystand a condensing agent consisting of trimethylamine hydrochloride.

CERTIFICA'E OF CORRECTION.

8. The process of producing an N-alkylated aromatic amine comprising the hydrogenation or a mixture oi an aromatic nitro compound WILLIAM S. EMERSDN.

November 6, 19 45- WILLIAM s. mason.

It is hereby certified that error appears in the printed specification of the above munbered patent requiring correction as follows: Page 3 secand column, line 27, for'"pressure" read --presenoe-; line 114., for "aoitities" read --aoi.dities--;

page it, first column, and that the said Letters Petent should be read with this correction therein that the same may conform to the record of the case in the Patent Office.

Signed and sealed this 5th day of F ruary, A. D. 19146.

(Seal) Leslie Frazer i First Assistant Camissioner of Patents. 

